A number of peptidic agents were designed, synthesized and tested in enzyme inhibition assays against the HIV-1 viral protease. 1. Design strategy utilized the generation of anti-sense peptides to six functionally significant regions of the enzyme. Of 66 peptides synthesized, 52 have been tested to date. The best inhibitors were found to be the hydropathically optimized, anti-sense peptides to the flap and the alpha helical region, and the peptides directed to bind to the polyprotein cleavage site (IC50 = 160-300 Micro). Several all-D configuration peptides were effective as well. 2. Two cyclic substrate-based peptides and two of their linear analogs were synthesized to examine the effect of a constrained turn conformation at the enzymic cleavage site. 3. Ten short D- and L- configuration peptides, several of which contained gamma-glutamyl or beta-aspartyl building blocks at the cleavage site, were prepared as potential inhibitors. Laminin is a large extracellular multidomain glycoprotein. Of the various active sites, the Ile-Lys-Val-Ala-Val (IKVAV) region in the A chain of laminin is associated with promoting cell attachment, migration, and collagenase IV induction. 1. We synthesized a heterotrimeric disulfide-linked 95-mer peptide encompassing the IKVAV region which also contained the highly alpha-helical 30-mer segments of both the B1 and B2 subunits. Competitive cell binding assays indicated enhanced receptor activity of the A chain when attached to the more structurally rigid B1-B2 chains. 2. Ten anti-sense peptides and several all-D configuration analogs of three receptor segments were prepared as potential inhibitors.
